High levels of C-reactive protein (CRP), an inflammation marker, were seen in soldiers who later developed post-traumatic stress disorder, researchers said.

by John Gever John Gever,Deputy Managing Editor, MedPage Today
February 27, 2014

Action Points

Note that this propsective cohort study demonstrated that higher baseline pre-deployment CRP levels were associated with post-deployment PTSD among Marines.

Be aware that there was a similar rate of PTSD symptoms pre- and post-deployment; in this light CRP might have served simply as a marker of pre-existing anxiety.

High levels of C-reactive protein (CRP), an inflammation marker, were seen in soldiers who later developed post-traumatic stress disorder, researchers said.

Among U.S. Marines and Navy personnel who consented to participate in a prospective study, each 10-fold increment in CRP levels at pre-deployment baseline was associated with a 51% increased likelihood of showing at least one PTSD symptom after deployment to Iraq or Afghanistan (odds ratio 1.51, 95% CI 1.15-1.97, P=0.003), reported Dewleen Baker, MD, of the VA Healthcare System in San Diego, and colleagues.

"If peripheral inflammation contributes to the development of PTSD, interventions to decrease inflammation, such as dietary or lifestyle modifications, might ameliorate the severity of this disorder," they wrote.

Paul E. Schulz, MD, of the University of Texas Health Science Center in Houston, who was not involved with the study, told MedPage Today that a clinical study "to investigate whether lowering CRP leads to a reduced incidence of developing PTSD" would help confirm a cause-and-effect relationship.

Another scholar not associated with the study said it highlighted an exciting area in PTSD research.

"The immune system is really a very complex part of the body, and I think we are just now beginning to understand its role in interactions with psychiatric illness," said Bruce Capehart, MD, of Duke University.

But he suggested that it would be premature to accept the current study as proof that inflammation is causative in PTSD.

He pointed to a lack of "dose-response" in the study -- in particular, that participants with baseline CRP levels higher than 10 ng/mL (well above the mean of 1.93 ng/mL) did not show significantly higher risk of PTSD than those with lower but still above-average CRP values.

"To look at it as one-way causation may not be that simple," Capehart said. "We may be looking at a two-way relationship there. Maybe there is a susceptibility there for some people to have a modestly elevated inflammatory state and a simultaneous greater risk for developing an anxiety disorder."

Study Design and Results

The analysis was part of the prospective Marine Resiliency Study, in which a total of 2,610 Marines and Navy sailors in four cohorts were recruited prior to war-theater deployment for baseline testing and subsequent medical and psychiatric follow-up. Participants were considered physically healthy at baseline.

Psychiatric follow-up was conducted after the conclusion of 7-month deployments at 3 months and again at 6 months. Data from both visits were available for 1,617 participants.

Mean participant age was about 23 but ranged from 18 to 48. CRP levels at baseline averaged 1.93 ng/mL (SD 3.31); the median level was 0.79 and the full range was 0.03 to 28.53. About half the cohort had been deployed before and the median time in military service was 3 years.

PTSD was evaluated with the Clinician-Administered PTSD Scale (CAPS); mean baseline scores were 14.89 (SD 15.37). Other psychiatric assessments included the Beck anxiety and depression scales. Participants were asked about deployment-related trauma at the 3-month visit.

Overall, the prevalence of PTSD did not change markedly post- versus pre-deployment. Diagnoses of PTSD were made in 4.7% of participants at baseline and in 6.3% and 5.1% at the 3- and 6-month evaluations after conclusion of deployment.

Baker and colleagues used a statistical method called zero-inflated negative binomial regression for their analyses of baseline factors in association with post-deployment CAPS scores. This was intended to compensate for data distributions "that have an excess of zeroes in addition to being positively skewed," they explained.

Under this method, measures of combat exposure and potentially traumatic battlefield experiences were significantly associated with CAPS scores at the 3-month post-deployment visit, with odds ratios of 1.03 (95% CI 1.01-1.05) and 1.08 (95% CI 1.03-1.13), respectively in a "zero model" indicating presence versus absence of any PTSD symptom.

In a "count model," indicating the extent of symptoms when present, scores for combat exposure, battlefield experience, and 10-fold increment in CRP were associated with post-deployment CAPS score as follows:

Combat exposure: OR 1.01 (P=0.001)

Battlefield experience: OR 1.04 (P<0.001)

Log CRP: OR 1.06 (P=0.09)

Looking at the data more simply, Baker and colleagues calculated that, after adjusting for combat exposure and battlefield experience scores, those with PTSD symptoms at the 6-month visit had mean baseline CRP levels of 1.0 ng/mL, versus about 0.77 ng/mL for those without post-deployment symptoms (P<0.05).

What Does It Mean?

Schulz said the inflammation-PTSD relationship was definitely plausible on the basis of several lines of research. For example, he told MedPage Today in an email, previous traumatic brain injury is a known risk factor for PTSD, and the mechanism may involve chronic brain inflammation resulting from the injury. Other lines of research have implicated immunological factors in promoting susceptibility to PTSD, he said.

But he acknowledged that CRP in the study could also have served as a marker for pre-existing stress and anxiety.

"Several of the papers we reviewed as part of a 'review of the risk factors for PTSD' suggested that a personal history of anxiety, a family history of anxiety, and a family history of depression, are risk factors for developing PTSD," Schulz said. He also noted that previous research had identified dozens of other risk factors for PTSD.

Psychologist David Blackburn, PhD, of Temple Mental Health Center in Temple, Texas, part of the Scott & White Healthcare system, who also was not involved with the study, told MedPage Today that future investigations into the relationship should take a broader perspective.

"I think subsequent research needs to not only involve military members who have PTSD, but also civilians who also have PTSD; this would strengthen the study," he said in an email. "In addition, more longitudinal studies over longer periods of time would also strengthen the relationship [Baker and colleagues] are proposing."

Capehart said the complexity of the mind-body relationship when it comes to PTSD "makes it a very exciting time to be practicing psychiatry."

The study was funded by the U.S. government.

Authors declared they had no relevant financial interests.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner